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salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma
Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma John M. Weiler, MD*; Robert A. Nathan, MD†; Ned T. Rupp, MD‡; Christopher J. Kalberg, PhD§; Amanda Emmett, MS§; and Paul M. Dorinsky, MD§
Background: Exercise is a common trigger of asthma symptoms in patients with persistent asthma. Objective: To evaluate the protective effect of fluticasone/salmeterol against exercise-induced bronchospasm. Methods: Multicenter, randomized, double-blind, parallel-group trial of 192 asthma patients who used moderate-dose inhaled corticosteroids. Patients (aged 12–50 years; mean forced expiratory volume in 1 second [FEV1], 78% of predicted at baseline) were randomized to receive fluticasone/salmeterol (250/50 g twice daily) or fluticasone alone (250 g twice daily) via Diskus for 4 weeks. Exercise challenge tests were performed 1 and 8.5 hours after administration of the first (day 1) and last (week 4) doses of blinded study medication. Results: On day 1 and at week 4, mean ⫾ SEM values for the maximal percentage decline in FEV1 1 hour after drug administration were 11.4% ⫾ 1.5% and 10.9% ⫾ 1.5% for fluticasone/salmeterol compared with 20.0% ⫾ 1.7% and 18.4% ⫾ 1.8% for fluticasone (P ⬍ .001). At 8.5 hours, mean ⫾ SEM values on day 1 and at week 4 were 11.6% ⫾ 1.4% and 8.9% ⫾ 1.1%, respectively, for fluticasone/salmeterol and 12.6% ⫾ 1.6% and 12.9% ⫾ 1.4%, respectively, for fluticasone (P ⫽ .01 at week 4). More fluticasone-treated patients did not complete the 8.5-hour exercise challenges (36% on day 1 and 33% at week 4) compared with the fluticasone/salmeterol group (18% each) (Pⱕ .01). Improvements in peak expiratory flow rate and albuterol rescue-free days were significantly greater with fluticasone/salmeterol vs fluticasone over weeks 1 to 4 (P ⱕ .03). Conclusions: Consistent with the improvements in other measures of asthma control, long-term fluticasone/salmeterol therapy also provided protection against exercise-induced bronchospasm in patients with persistent asthma. Ann Allergy Asthma Immunol. 2005;94:65–72.
INTRODUCTION Previous studies1,2 have demonstrated that fluticasone/salmeterol administered via a single Diskus improves overall asthma control in patients who were symptomatic while receiving salmeterol alone or low-to-moderate doses of inhaled corticosteroids for the treatment of persistent asthma at study entry. These studies examined standard measures of asthma control, including pulmonary function, symptoms, use of albuterol as rescue medication, and asthma stability, to demonstrate improved clinical efficacy. However, no previous studies, to our knowledge, have evaluated the effect of fluticasone/salmeterol on symptoms that result from exercise in patients with persistent asthma. Physical activity is a common stimulus that may precipitate or aggravate airway obstruction in patients with asthma at all levels of severity.3 In patients with persistent asthma, exercise and other forms of activity often represent an important * University of Iowa, CompleWare Corporation, and Iowa Clinical Research Corporation, Iowa City, Iowa. † Asthma and Allergy Associates PC, Colorado Springs, Colorado. ‡ Asthma and Allergy Center of Charleston, Hilltop Research Center, Charleston, South Carolina. § GlaxoSmithKline, Research Triangle Park, North Carolina. This study was supported by a grant from GlaxoSmithKline. Received for publication February 4, 2004. Accepted for publication in revised form September 30, 2004.
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trigger that can lead to worsening symptoms of asthma.3 Indeed, the presence of exercise-induced symptoms indicates inadequate disease control4 and underlying airway hyperresponsiveness. Bronchodilators, long and short acting, have been used traditionally to prevent attacks of exercise-induced bronchospasm and to treat attacks when they occur.3–5 Inhaled corticosteroids have also been used to prevent attacks, and they probably work by attenuating airway inflammation and decreasing airway hyperresponsiveness, leading to a reduction in the severity of asthma symptoms induced by exercise.6 –9 Therefore, fluticasone/salmeterol, which has bronchodilator and anti-inflammatory properties, might be an effective controller for patients with persistent asthma who experience worsening of asthma symptoms associated with physical activity. The objective of this multicenter, randomized, double-blind, parallel-group study was to evaluate the effectiveness of regular treatment with fluticasone/salmeterol vs fluticasone alone administered via Diskus on preventing exercise-induced bronchospasm in symptomatic adolescents and adults receiving moderate-dose inhaled corticosteroids for the treatment of persistent asthma. METHODS Patient Selection Male and female patients aged 12 to 50 years with a diagnosis of asthma10 for at least 6 months before screening who had a
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forced expiratory volume in 1 second (FEV1) of 65% to 90% of predicted and who demonstrated a decrease in FEV1 of 20% or greater from baseline after standardized stepped exercise challenge testing were recruited for this study. Predicted FEV1 was based on Crapo predicted normal values for patients 18 years and older11 or Polgar predicted normal values for patients 12 to 17 years of age.12 For African American patients, predicted FEV1 values were race adjusted.13 In addition, each subject must have been taking 1 of the following inhaled corticosteroids at a constant dose for at least 30 days before screening (visit 1): fluticasone, 440 g/d via metered-dose inhaler or 500 g/d via powder inhaler; beclomethasone dipropionate, 462 to 672 g/d; triamcinolone acetonide, 1,100 to 1,600 g/d; flunisolide, 1,250 to 2,000 g/d; or budesonide, 600 to 800 g/d. Study Design and Conduct This randomized, double-blind, parallel-group study compared the effects of fluticasone/salmeterol, 250/50 g twice daily via Diskus, with those of fluticasone, 250 g twice daily via Diskus, on exercise-induced bronchospasm, morning peak expiratory flow rate (PEFR), and rescue albuterol use over 4 weeks. The protocol (SAS40025) was approved by institutional review boards at the 40 investigative sites (all in the United States), and informed consent was obtained from all study participants. Eligible patients discontinued the use of inhaled corticosteroids and received unblinded fluticasone, 250 g twice daily via Diskus, during a 2- to 5-week run-in period. To be eligible for randomization, patients had to demonstrate a decrease in FEV1 of 20% or greater on the first (at visit 1) and second (at visit 2) screening exercise challenge tests; visit 2 was conducted after 2 to 4 weeks of treatment with fluticasone, 250 g twice daily. Patients returned to the clinic 2 to 7 days after visit 2 and were randomized to receive either fluticasone/salmeterol, 250/50 g twice daily, or fluticasone, 250 g twice daily. At 1 and 8.5 hours after the initial dose of blinded study medication was administered, patients performed a stepped exercise challenge test similar to that performed at visits 1 and 2. After 4 weeks of treatment, the final exercise challenge tests were performed 1 and 8.5 hours after the last dose of blinded study medication was administered. Throughout the study, patients made daily recordings of their study medication use, rescue albuterol use, PEFR, and adverse events on diary cards. Exercise Challenge Testing The stepped exercise challenge test consisted of running on a treadmill; the speed and incline of the treadmill allowed the patient’s heart rate to reach 80% or more of maximum based on age and is similar to the challenge reported by Simons et al.14 To control for the effects of the temperature and humidity of the inspired air during exercise, the subjects inspired compressed air from a balloon reservoir bag (eg, a Douglas Bag) fitted with a 2-way, non-rebreathing valve and a mouth-
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piece or face mask. The temperature of the room was maintained at 20° C to 25° C. The guidelines for performing the stepped exercise challenge test were as follows: step 1 lasted 2 minutes, with a target heart rate of 50% of maximum for age achieved by a treadmill speed of 2.5 mph at no incline; step 2 lasted 2 minutes, with a target heart rate of 70% of maximum for age achieved by a treadmill speed of 66% of the target speed at an incline based on age; and step 3 lasted 6 minutes, with a target heart rate of 80% of maximum achieved by the target treadmill speed at an incline based on age. Progression between these steps was contingent on the absence of cardiovascular and pulmonary signs and symptoms. The subject’s electrocardiogram and heart rate were monitored continuously throughout the exercise challenge test. The treadmill incline did not exceed 15%. Subjects were permitted to eat a light meal between the 2 exercise challenge test assessments on treatment day 1 and at week 4, and the meal was to be completed at least 1 hour before the second exercise challenge test. Food and beverages that contain caffeine were not permitted, and each subject was to remain sedentary at the site between exercise challenge tests. Spirometry assessments were performed on treatment day 1 and at week 4: immediately before drug administration (double-blinded study medication), immediately before exercise challenge testing, and 5, 10, 15, 30, and 60 minutes after exercise challenge using standardized equipment. Triplicate FEV1 measurements were performed at each evaluation. The highest FEV1 at each evaluation was used. Before beginning the second exercise challenge evaluation on days 1 and 28 of treatment, a subject’s FEV1 must have returned to at least 65% of predicted. After completion of each exercise challenge, rescue with albuterol was required if a patient’s FEV1 decreased to 40% of predicted or less or, at the study investigator’s discretion, if a patient experienced significant worsening of asthma symptoms. Because residual therapeutic effects of the albuterol could persist and affect subsequent exercise challenge test results, patients were not permitted to complete the 8.5-hour exercise challenge if they received albuterol rescue after the 1-hour challenge. Treatments Fluticasone/salmeterol, 250/50 g twice daily (Advair Diskus; GlaxoSmithKline, Research Triangle Park, NC), and fluticasone, 250 g twice daily (Flovent Diskus; GlaxoSmithKline), were administered in a double-blind manner. All patients received albuterol (Ventolin Inhalation Aerosol; GlaxoSmithKline) to use as needed to relieve breakthrough symptoms. Statistical Methods Based on data from previous studies5,15 that evaluated exercise-induced bronchospasm, it was estimated that 85 patients per treatment arm would provide 90% power to detect a significant difference in maximal percentage decrease in
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FEV1 of 6% between the 2 treatment groups based on a 2-sample, 2-sided t test at a significance level of P ⱕ .05. The primary measure of efficacy was maximal percentage decrease in FEV1 after the 8.5-hour exercise challenge test on treatment day 1 and at week 4. At baseline and at each stage after exercise, the test with the best FEV1 was selected; maximal percentage decline in FEV1 was defined as the percentage change from the preexercise baseline FEV1 to the minimum FEV1, collected within 1 hour of exercise challenge testing (selecting the best effort at each time). Exercise challenge tests were performed 1 and 8.5 hours after the first dose of blinded study drug was administered on treatment day 1 and 1 and 8.5 hours after the last dose of blinded study drug was administered at week 4. For each 1- and 8.5-hour exercise challenge test on treatment day 1 and at week 4, preexercise baseline FEV1 was measured approximately 1 and 8.5 hours after administration of double-blinded study medication (ie, immediately before exercise challenge testing). Secondary analyses included a categorical evaluation of the maximal percentage decline in FEV1 after exercise challenge testing, the time to return to within 5% of the preexercise value, the change from baseline in morning PEFR during the 4 weeks of treatment, and the change from baseline in the percentage of albuterol rescue–free days (defined as a day with no supplemental albuterol use) over the 4 weeks of treatment. Recovery time was defined as the time to return to within 5% of the preexercise baseline value from the time of the maximal percentage decline and was estimated with linear interpolation. If a patient’s FEV1 did not decrease 5%, recovery time was set at 0 minutes. If a patient was rescued and did not perform a postexercise FEV1 measure or did not return to within 5% of the preexercise baseline value, recovery time was set at 80 minutes.
Analysis of covariance models that include terms for treatment, investigator, and baseline were used to perform between–treatment group comparisons of continuous variables. Treatment group comparisons of categorical variables were examined using the Cochran-Mantel-Haenszel test. All statistical tests used a 2-sided hypothesis of no difference between treatment groups at a significance level of P ⬍ .05. The primary population for all statistical analyses was the intent-to-treat (ITT) population, which consisted of all patients randomized to receive study drug. All data collected for these patients, including those who discontinued study participation, were included. RESULTS A total of 192 patients were randomized to double-blind treatment: 102 to fluticasone/salmeterol, of whom 98 (96%) completed the study, and 90 to fluticasone, of whom 87 (97%) completed the study. The treatment groups were similar at baseline with respect to demographics, asthma and smoking history, and pulmonary function (Table 1). At screening, patients in both groups had a mean FEV1 of 78% of predicted, and mean ⫾ SEM maximal decreases in FEV1 after exercise challenge were 31.8% ⫾ 0.9% and 31.4% ⫾ 1.0% in the fluticasone/salmeterol and fluticasone groups, respectively. Most patients (82%) were using fluticasone before enrollment. Exercise Challenge Testing At visit 2, which was after 2 to 4 weeks of treatment with fluticasone, 250 g twice daily, values for the mean ⫾ SEM maximal decline in FEV1 after exercise challenge were 29.1% ⫾ 0.9% and 31.2% ⫾ 1.1% for patients who subsequently
Table 1. Baseline Demographic and Clinical Characteristics of the Study Population Characteristic Age, mean (range), y Women, % Race/ethnicity, No. (%) White Black Asian Hispanic Other Never used tobacco, %* History of asthma ⱖ 15 y, % Asthma-related emergency care, previous year, % Asthma-related hospitalization, previous year, % FEV1, mean ⫾ SEM, L FEV1, mean ⫾ SEM, % predicted Maximal postexercise decline in FEV1 at screening, mean ⫾ SEM, %
Fluticasone/salmeterol, 250/50 g (n ⴝ 102)
Fluticasone, 250 g (n ⴝ 90)
29 (12–50) 65 (64)
29 (12–50) 52 (58)
77 (75) 16 (16) 1 (⬍1) 6 (6) 2 (2) 83 64 18 6 2.72 ⫾ 0.06 78.2 ⫾ 0.7 31.8 ⫾ 0.9
62 (69) 22 (24) 0 4 (4) 2 (2) 87 54 11 3 2.72 ⫾ 0.07 77.8 ⫾ 0.8 31.4 ⫾ 1.0
Abbreviation: FEV1, forced expiratory volume in 1 second. * Patients were excluded if they had more than 10 pack-years of smoking or had smoked in the past year.
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were randomized to receive fluticasone/salmeterol and fluticasone, respectively. At visit 3 (treatment day 1), values for the mean ⫾ SEM maximal decline in FEV1 1 and 8.5 hours after administration of the first dose of study medication were 11.4% ⫾ 1.5% and 11.6% ⫾ 1.4%, respectively, for fluticasone/salmeterol and 20.0% ⫾ 1.7% and 12.6% ⫾ 1.6%, respectively, for fluticasone (P ⬍ .001 for comparison of fluticasone/salmeterol and fluticasone at 1 hour and P ⫽ .44 at 8.5 hours) (Fig 1). At week 4, values for the mean ⫾ SEM maximal decline in FEV1 at 1 and 8.5 hours after administration of the last dose of study medication were 10.9% ⫾ 1.5% and 8.9% ⫾ 1.1%, respectively, for fluticasone/salmeterol and 18.4% ⫾ 1.8% and 12.9% ⫾ 1.4%, respectively, for fluticasone (P ⱕ .01 for comparisons of fluticasone/salmeterol and fluticasone at 1 and 8.5 hours) (Fig 1). A significantly greater percentage of patients in the fluticasone group did not complete the 8.5hour exercise challenge test on day 1 or at week 4 compared with the fluticasone/salmeterol group (P ⱕ .01). Specifically, on treatment day 1 and at week 4, 36% and 33% of patients, respectively, in the fluticasone group did not complete the 8.5-hour exercise challenge test. By contrast, 18% of patients treated with fluticasone/salmeterol did not complete the 8.5hour exercise challenge test on treatment day 1 and at week 4. The primary reason patients did not complete the 8.5-hour challenge was the use of albuterol after the 1-hour challenge according to protocol-defined rescue criteria. On treatment day 1, 76% and 82% of patients in the fluticasone/salmeterol group had less than a 20% decrease in FEV1 after the 1- and 8.5-hour exercise challenges, respectively, compared with 54% and 81% of patients in the fluti-
casone group (P ⬍ .001 at 1 hour). At week 4, 80% and 90% of patients in the fluticasone/salmeterol group had less than a 20% decrease in FEV1 after the 1- and 8.5-hour exercise challenges, respectively, compared with 60% and 78% of patients in the fluticasone group (P ⱕ .04 at 1 and 8.5 hours). Additional categorical analyses of patients by maximal decline in FEV1 are given in Table 2. Recovery time, expressed as the time to return to within 5% of the preexercise, postdose baseline values from the maximum percentage decline in FEV1, is given in Table 3. On day 1 and at week 4, mean ⫾ SEM recovery times after the 1- and 8.5-hour challenges ranged from 17.1 ⫾ 2.9 to 22.4 ⫾ 3.1 minutes for the fluticasone/salmeterol group and 28.0 ⫾ 3.9 to 33.7 ⫾ 3.4 minutes for the fluticasone group (P ⱕ .045 for the 1-hour comparisons on day 1 and at week 4 and for the 8.5-hour comparisons at week 4). PEF and Albuterol Use Baseline mean ⫾ SEM values for morning PEFR were similar: 399.7 ⫾ 10.1 L/min and 426.4 ⫾ 13.7 L/min for the fluticasone/salmeterol and fluticasone groups, respectively. Over the 4-week treatment period, patients receiving fluticasone/salmeterol had a significantly greater mean ⫾ SEM increase in morning PEFR (19.2 ⫾ 3.4 L/min) compared with patients receiving fluticasone (6.3 ⫾ 4.1 L/min) (P ⫽ .03). The mean ⫾ SEM percentage of albuterol rescue–free days was also similar between the 2 treatment groups at baseline: 17.0% ⫾ 2.7% and 13.1% ⫾ 2.2% for the fluticasone/salmeterol and fluticasone groups, respectively. During the 4-week treatment period, patients in the fluticasone/salmeterol group
Figure 1. Mean maximal percentage decline in forced expiratory volume in 1 second after exercise challenge testing at 1 and 8.5 hours on treatment day 1 and at week 4 in the fluticasone/salmeterol, 250/50 g, and fluticasone, 250 g, groups. Asterisk indicates P ⱕ .01 vs fluticasone; dagger, P ⫽ .44 vs fluticasone. Error bars represent SEM.
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Table 2. Categorical Analysis of Patients by Percentage Decrease in Postexercise FEV1 1h Characteristic
8.5 h
Fluticasone, Fluticasone/salmeterol, Fluticasone, Fluticasone/salmeterol, 250 g (n ⴝ 90) 250/50 g (n ⴝ 102) 250 g (n ⴝ 90) 250/50 g (n ⴝ 102)
Patients completing the exercise challenge, No.* Postexercise decrease in FEV1, No. (%) ⬍10% 10% to ⬍15% 15% to ⬍20% 20% to ⬍25% ⱖ25%
Treatment day 1 90
100
84
58
45 (54) 14 (17) 10 (12) 4 (5) 11 (13)
29 (50) 10 (17) 8 (14) 4 (7) 7 (12)
59 (59) 14 (14) 3 (3) 7 (7) 17 (17)
32 (36) 6 (7) 11 (12) 9 (10) 32 (26)
98
86
84
60
66 (67) 11 (11) 1 (1) 5 (5) 15 (15)
35 (41) 10 (12) 7 (8) 3 (3) 31 (36)
59 (70) 10 (12) 7 (8) 2 (2) 6 (7)
30 (50) 10 (17) 7 (12) 4 (7) 9 (15)
Week 4 Patients completing the exercise challenge, No.* Postexercise decrease in FEV1, No. (%) ⬍10% 10% to ⬍15% 15% to ⬍20% 20% to ⬍25% ⱖ25%
Abbreviation: FEV1, forced expiratory volume in 1 second. *Two and 4 patients in the fluticasone/salmeterol group did not complete the 1-hour challenge on treatment day 1 and at week 4, respectively; 4 patients in the fluticasone group did not complete the 1-hour challenge at week 4. Table 3. Postexercise Recovery Time* Exercise challenge Treatment day 1 1h 8.5 h Week 4 1h 8.5 h
Fluticasone/salmeterol, 250/50 g
Fluticasone, 250 g
Patients, No.†
Recovery time, mean ⴞ SEM, min
Patients, No.†
Recovery time, mean ⴞ SEM, min
P value
102 87
19.7 ⫾ 2.8 22.4 ⫾ 3.1
90 66
33.7 ⫾ 3.4 28.0 ⫾ 3.9
.002 .562
98 87
18.5 ⫾ 2.8 17.1 ⫾ 2.9
87 67
31.7 ⫾ 3.4 28.6 ⫾ 3.8
.009 .045
* Recovery time was defined as the time to return to 5% of the preexercise baseline value from the time of the maximal percentage decline and was estimated using linear interpolation. † The number of patients who initiated an exercise challenge.
experienced a significantly greater increase in the mean ⫾ SEM percentage of rescue-free days vs patients in the fluticasone group (15.8% ⫾ 2.8% vs 7.6% ⫾ 2.9%; P ⫽ .02) (Fig 2). Adverse Events During the double-blind treatment period, 28 patients (27%) in the fluticasone/salmeterol group and 24 patients (27%) in the fluticasone group reported at least 1 adverse event. Adverse events reported by 3% or more of patients in either treatment group were headaches (6% with fluticasone/salmeterol and 4% with fluticasone), common cold (3% in each treatment group), upper respiratory tract infection (⬍1% with fluticasone/salmeterol and 4% with fluticasone), and sore throat (⬍1% with fluticasone/salmeterol and 3% with fluticasone).
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Seven patients (7%) receiving fluticasone/salmeterol and 4 (4%) receiving fluticasone reported adverse events that were considered by the reporting investigator to be drug related. Drug-related adverse events reported by more than 1% of patients in either treatment group were Candida (2% and 1% in the fluticasone/salmeterol and fluticasone groups, respectively) and headaches (3% and 0% in the fluticasone/salmeterol and fluticasone groups, respectively). Two patients (2%) receiving fluticasone/salmeterol and 1 (1%) receiving fluticasone were withdrawn from the study due to an adverse event. In the fluticasone/salmeterol group, 1 patient was withdrawn to undergo elective cosmetic surgery and 1 for “fainting,” which was considered by the investigator to possibly be related to the study medication. One patient in the fluticasone group withdrew because of symptoms associated with a viral upper respiratory tract infection. All
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Figure 2. Mean percentage of rescue-free days over 4 weeks of treatment. Asterisk indicates P ⱕ .04 for fluticasone/salmeterol, 250/50 g, vs fluticasone, 250 g.
events resolved by the end of the study. Only 1 exacerbation of asthma was reported in this study. It occurred in a patient in the fluticasone/salmeterol group and was due to a respiratory tract infection. There were no serious adverse events. DISCUSSION The results of this study demonstrate that in patients who were using moderate-dose inhaled corticosteroids for treatment of persistent asthma and demonstrated a decrease in FEV1 of at least 20% after exercise challenge before randomization, treatment with fluticasone/salmeterol protected against exercise-induced bronchospasm in most patients 1 and 8.5 hours after drug administration. Compared with fluticasone, the protective effect was greatest after 1 hour of treatment, with smaller differences observed after 8.5 hours. However, the protective effects of fluticasone/salmeterol therapy at 1 and 8.5 hours were sustained during long-term dosing, showing no evidence of diminution of effect during the 4-week study. The results of the present study need to be evaluated in light of differences in study design between this study and other exercise challenge studies. First, treatments for exercise-induced bronchospasm are most often studied in patients with near-normal lung function. Such patients have asthma symptoms that are triggered primarily by exercise, and they often have few, if any, other symptoms or persistent asthma.5,15–20 By contrast, patients in the present study had moderate persistent asthma, and they all required moderate doses of inhaled corticosteroids at study entry. Note that patients with persistent asthma who require daily controller therapy can experience worsening asthma symptoms that are triggered by activity or exercise as well as other common asthma triggers.3 This was true of the patients in this study, who had not only significant decreases in FEV1 after exercise challenge testing but also less than 20% rescue-free days during the run-in period.
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Second, the decreases in FEV1 observed after exercise challenge testing were greater in this study than have been reported in previous studies,5,15,16 in which patients generally had characteristics of mild asthma (baseline FEV1, 85%– 89% of predicted). For example, Kemp et al5 demonstrated that 30 minutes after dosing with salmeterol, 50 g, mean maximal percentage declines in FEV1 were only 5%. Likewise, Newnham et al16 evaluated the effect of salmeterol therapy on exercise-induced bronchospasm and found that the mean maximal percentage fall in FEV1 was only 0.8% an hour after drug administration. Similar results have been shown in pediatric patients with mild asthma.15 Relative to the present study, the smaller declines in FEV1 demonstrated in these other studies may, in part, reflect differences in baseline asthma severity in the study populations. Finally, inclusion of patients with moderate persistent asthma had a major impact on the ability of patients to complete 2 exercise challenge tests on the same treatment day. This was a more prominent finding in the fluticasone group. Approximately twice the number of patients in the fluticasone group did not complete the 8.5-hour exercise challenge on treatment day 1 and at week 4 (36% and 33%, respectively) compared with the fluticasone/salmeterol group (18% at each visit). This disparity was likely due to a lower level of protection against exercise-induced bronchospasm with fluticasone alone for the patient population as a whole. In the fluticasone group, the decreases in FEV1 at the 1-hour challenge (mean, 19.2%) were greater than at the 8.5-hour challenge (mean, 12.8%). This is in contrast to the fluticasone/salmeterol group, in which the decrease in FEV1 at 1 and 8.5 hours was similar (mean, 11.2% and 10.3%, respectively). Thus, the treatment differences were smaller between fluticasone/salmeterol and fluticasone at 8.5 hours compared with at 1 hour. The smaller treatment difference at 8.5 hours was not due to a loss of effectiveness with fluticasone/salmeterol. Rather, the smaller treatment difference was due to the fact
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that many patients with the greatest reductions in FEV1 after the 1-hour challenge in the fluticasone group had to be rescued with albuterol and thus did not participate in the 8.5-hour challenge. The difference in response at 1 and 8.5 hours with fluticasone is difficult to explain pharmacologically, because the effect of fluticasone should not differ during this short period. Analysis of patients in the fluticasone group who completed both exercise challenges indicates that they had similar responses at 1 and 8.5 hours. For these completers, an average decrease in FEV1 of 12.8% was observed at 1 and 8.5 hours on treatment day 1. For the fluticasone/salmeterol group, the mean decrease in FEV1 at 1 and 8.5 hours for patients who completed both challenges averaged 7.5% and 10.3%, respectively. Similar to the findings in the ITT population, these reductions were significantly less compared with those in the fluticasone group at all times except 8.5 hours on treatment day 1 (P ⱕ .01). Thus, in the ITT population and in the subgroup of the ITT population that completed both challenges, a significantly greater protective effect was observed with fluticasone/salmeterol therapy 8.5 hours after administration of the last dose of study medication, indicating that the protective effect of this drug was maintained with regular use. Patients who completed both exercise challenge tests had a different exercise response compared with those who completed only the 1-hour challenge. For example, patients in the fluticasone/salmeterol (14%) and fluticasone (29%) groups who completed only the 1-hour challenge had mean maximal declines in FEV1 of 33.5% and 31.9%, respectively. For these patients, neither treatment provided adequate protection against exercise-induced bronchospasm based on the study protocol (ie, decrease in FEV1 to ⱕ40% of predicted or based on investigator discretion for worsening symptoms of asthma), and additional treatment was required. If these patients had completed both exercise challenges, it is unclear whether the results of this study would have differed. However, it would likely have resulted in a greater mean decrease in the fluticasone group due to the greater number of patients who did not complete the second exercise challenge compared with the fluticasone/salmeterol group. The salmeterol component of fluticasone/salmeterol is indicated for the treatment of exercise-induced bronchospasm, and a single dose of salmeterol provides protection in most patients for up to 12 hours.5,15,16 Long-term dosing studies10,18 –21 have shown a diminution of effect with the use of inhaled long-acting 2-agonists over time. However, long-term use of long-acting -agonists as monotherapy for exercised-induced bronchospasm in patients with persistent asthma is not appropriate, so the applicability of many of these previous studies to patients with persistent asthma is limited. Inhaled corticosteroids have been shown to reduce the severity of exercise-induced bronchospasm.6 –9 The mechanism of action for inhaled corticosteroids in this setting is less clear than the mechanism of action for -agonists but is likely due to nonspecific reductions in bronchial hyperresponsiveness and reduced inflammation.21–24 However, regardless of
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the precise mechanism, optimal benefit is obtained when an inhaled corticosteroid is used in combination with an inhaled long-acting -agonist. In conclusion, the results of this study demonstrate that regular use of fluticasone/salmeterol, 250/50 g twice daily, resulted in protection against exercise-induced bronchospasm in patients using moderate-dose inhaled corticosteroids for the treatment of persistent asthma. Significantly greater protection was observed with fluticasone/salmeterol therapy 8.5 hours after administration of the last treatment dose at week 4 compared with fluticasone therapy, indicating that the protective effect of fluticasone/salmeterol was maintained with long-term dosing. These results suggest that patients with persistent asthma, for whom physical activity is a trigger of asthma symptoms, may receive additional benefit from the use of fluticasone/salmeterol. ACKNOWLEDGMENTS We thank Shawn Jones, Patricia Matthews, Laura Sutton, and Cedric Grigg for assisting with the preparation of the manuscript and the following clinical investigators for their expertise and contributions: Theodore Lee, MD, Steven F. Weinstein, MD, Andrew J. Pedinoff, MD, Paul Chervinsky, MD, William W. Busse, MD, Edward Kerwin, MD, Frank S. Virant, MD, Arthur C. DeGraff, MD, Tom Harper, MD, Kenneth T. Kim, MD, David S. Pearlman, MD, Edward LeDoux, MD, Robert Noveck, MD, Sheldon Spector, MD, David I. Bernstein, MD, Edwin A. Bronsky, MD, Jonathan Corren, MD, Michael Natalino, MD, Anjuli Nayak, MD, Richard Rosenthal, MD, William N. Sokol, MD, Martha White, MD, Richard ZuWallack, MD, John Andrew Grant, MD, Craig F. LaForce, MD, Richard Weber, MD, Charles Fogarty, MD, Barry Miskin, MD, Jacob L. Pinnas, MD, Eugene F. Schwartz, MD, David Elkayam, MD, Harold B. Kaiser, MD, Phillip E. Korenblat, MD, Nancy K. Ostrom, MD, Michael P. Pacin, MD, Lewis Smith, MD, and Mark Wencel, MD. REFERENCES 1. Shapiro G, Lumry W, Wolfe J, et al. Combined salmeterol 50 g and fluticasone propionate 250 g in the Diskus device for the treatment of asthma. Am J Respir Crit Care Med. 2000;161: 527–534. 2. Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2000;105: 1108 –1116. 3. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; April 1997. 4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; February 2002. NIH publication 02–3659. 5. Kemp JP, Dockhorn RJ, Busse WW, Bleecker ER, Van As A. Prolonged effect of inhaled salmeterol against exercise-induced
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6.
7.
8.
9.
10. 11. 12. 13. 14.
15.
bronchospasm. Am J Respir Crit Care Med. 1994;150: 1612–1615. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. Thorax. 1991;46:811– 816. Freezer NJ, Croasdell H, Doull IJ, Holgate ST. Effect of regular inhaled beclomethasone on exercise and methacholine airway responses in school children with recurrent wheeze. Eur Respir J. 1995;8:1488 –1493. Vidal C, Fernandez-Ovide E, Pineiro J, Nunez R, GonzalezQuintela A. Comparison of montelukast versus budesonide in the treatment of exercise-induced bronchoconstriction. Ann Allergy Asthma Immunol. 2001;86:655– 658. Hofstra WB, Neijens HJ, Duiverman EJ, et al. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Pediatr Pulmonol. 2000;29:415– 423. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987;136:225–244. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meets ATS recommendations. Am Rev Respir Dis. 1981;123:659 – 664. Polgar G, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia, PA: WB Saunders Co; 1971. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis. 1991;144:1202–1208. Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exerciseinduced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics. 1997;99:655– 659. Blake K, Pearlman DS, Scott C, Wang Y, Stahl E, Arledge T. Prevention of exercise-induced bronchospasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol. Ann Allergy Asthma Immunol. 1999;82:205–211.
16. Newnham DM, Ingram CG, Earnshaw J, Palmer JB, Dhillon DP. Salmeterol provides prolonged protection against exerciseinduced bronchoconstriction in a majority of patients with mild, stable asthma. Respir Med. 1993;87:439 – 444. 17. Nelson J, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden ER Jr. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med. 1998;339:141–146. 18. Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Ann Intern Med. 2000;132:97–104. 19. Villaran C, O’Neill SJ, Helbling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol. 1999;104:547–553. 20. Garcia R, Guerra P, Feo F, et al. Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm. J Investig Allergy Clin Immunol. 2001;11:176 –182. 21. Trigg CJ, Manolitsas ND, Wang J, et al. Placebo-controlled immunopathologic study of 4 months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17–22. 22. Olivieri D, Chetta A, Del Donno M, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebocontrolled study. Am J Respir Crit Care Med. 1997;155: 1864 –1871. 23. Barnes PJ. Current issues for establishing inhaled corticosteroids as the antiinflammatory agents of choice in asthma. J Allergy Clin Immunol. 1998;101:427– 433. 24. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054 –1063.
Requests for reprints should be addressed to: John M. Weiler, MD Iowa Clinical Research Corporation PO Box 2959 Iowa City, IA 52244-2959 E-mail: [email protected]
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Background: Exercise is a common trigger of asthma symptoms in patients with persistent asthma. Objective: To evaluate the protective effect of fluticasone/salmeterol against exercise-induced bronchospasm. Methods: Multicenter, randomized, double-blind, parallel-group trial of 192 asthma patients who used moderate-dose inhaled corticosteroids. Patients (aged 12–50 years; mean forced expiratory volume in 1 second [FEV1], 78% of predicted at baseline) were randomized to receive fluticasone/salmeterol (250/50 g twice daily) or fluticasone alone (250 g twice daily) via Diskus for 4 weeks. Exercise challenge tests were performed 1 and 8.5 hours after administration of the first (day 1) and last (week 4) doses of blinded study medication. Results: On day 1 and at week 4, mean ⫾ SEM values for the maximal percentage decline in FEV1 1 hour after drug administration were 11.4% ⫾ 1.5% and 10.9% ⫾ 1.5% for fluticasone/salmeterol compared with 20.0% ⫾ 1.7% and 18.4% ⫾ 1.8% for fluticasone (P ⬍ .001). At 8.5 hours, mean ⫾ SEM values on day 1 and at week 4 were 11.6% ⫾ 1.4% and 8.9% ⫾ 1.1%, respectively, for fluticasone/salmeterol and 12.6% ⫾ 1.6% and 12.9% ⫾ 1.4%, respectively, for fluticasone (P ⫽ .01 at week 4). More fluticasone-treated patients did not complete the 8.5-hour exercise challenges (36% on day 1 and 33% at week 4) compared with the fluticasone/salmeterol group (18% each) (Pⱕ .01). Improvements in peak expiratory flow rate and albuterol rescue-free days were significantly greater with fluticasone/salmeterol vs fluticasone over weeks 1 to 4 (P ⱕ .03). Conclusions: Consistent with the improvements in other measures of asthma control, long-term fluticasone/salmeterol therapy also provided protection against exercise-induced bronchospasm in patients with persistent asthma. Ann Allergy Asthma Immunol. 2005;94:65–72.
INTRODUCTION Previous studies1,2 have demonstrated that fluticasone/salmeterol administered via a single Diskus improves overall asthma control in patients who were symptomatic while receiving salmeterol alone or low-to-moderate doses of inhaled corticosteroids for the treatment of persistent asthma at study entry. These studies examined standard measures of asthma control, including pulmonary function, symptoms, use of albuterol as rescue medication, and asthma stability, to demonstrate improved clinical efficacy. However, no previous studies, to our knowledge, have evaluated the effect of fluticasone/salmeterol on symptoms that result from exercise in patients with persistent asthma. Physical activity is a common stimulus that may precipitate or aggravate airway obstruction in patients with asthma at all levels of severity.3 In patients with persistent asthma, exercise and other forms of activity often represent an important * University of Iowa, CompleWare Corporation, and Iowa Clinical Research Corporation, Iowa City, Iowa. † Asthma and Allergy Associates PC, Colorado Springs, Colorado. ‡ Asthma and Allergy Center of Charleston, Hilltop Research Center, Charleston, South Carolina. § GlaxoSmithKline, Research Triangle Park, North Carolina. This study was supported by a grant from GlaxoSmithKline. Received for publication February 4, 2004. Accepted for publication in revised form September 30, 2004.
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trigger that can lead to worsening symptoms of asthma.3 Indeed, the presence of exercise-induced symptoms indicates inadequate disease control4 and underlying airway hyperresponsiveness. Bronchodilators, long and short acting, have been used traditionally to prevent attacks of exercise-induced bronchospasm and to treat attacks when they occur.3–5 Inhaled corticosteroids have also been used to prevent attacks, and they probably work by attenuating airway inflammation and decreasing airway hyperresponsiveness, leading to a reduction in the severity of asthma symptoms induced by exercise.6 –9 Therefore, fluticasone/salmeterol, which has bronchodilator and anti-inflammatory properties, might be an effective controller for patients with persistent asthma who experience worsening of asthma symptoms associated with physical activity. The objective of this multicenter, randomized, double-blind, parallel-group study was to evaluate the effectiveness of regular treatment with fluticasone/salmeterol vs fluticasone alone administered via Diskus on preventing exercise-induced bronchospasm in symptomatic adolescents and adults receiving moderate-dose inhaled corticosteroids for the treatment of persistent asthma. METHODS Patient Selection Male and female patients aged 12 to 50 years with a diagnosis of asthma10 for at least 6 months before screening who had a
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forced expiratory volume in 1 second (FEV1) of 65% to 90% of predicted and who demonstrated a decrease in FEV1 of 20% or greater from baseline after standardized stepped exercise challenge testing were recruited for this study. Predicted FEV1 was based on Crapo predicted normal values for patients 18 years and older11 or Polgar predicted normal values for patients 12 to 17 years of age.12 For African American patients, predicted FEV1 values were race adjusted.13 In addition, each subject must have been taking 1 of the following inhaled corticosteroids at a constant dose for at least 30 days before screening (visit 1): fluticasone, 440 g/d via metered-dose inhaler or 500 g/d via powder inhaler; beclomethasone dipropionate, 462 to 672 g/d; triamcinolone acetonide, 1,100 to 1,600 g/d; flunisolide, 1,250 to 2,000 g/d; or budesonide, 600 to 800 g/d. Study Design and Conduct This randomized, double-blind, parallel-group study compared the effects of fluticasone/salmeterol, 250/50 g twice daily via Diskus, with those of fluticasone, 250 g twice daily via Diskus, on exercise-induced bronchospasm, morning peak expiratory flow rate (PEFR), and rescue albuterol use over 4 weeks. The protocol (SAS40025) was approved by institutional review boards at the 40 investigative sites (all in the United States), and informed consent was obtained from all study participants. Eligible patients discontinued the use of inhaled corticosteroids and received unblinded fluticasone, 250 g twice daily via Diskus, during a 2- to 5-week run-in period. To be eligible for randomization, patients had to demonstrate a decrease in FEV1 of 20% or greater on the first (at visit 1) and second (at visit 2) screening exercise challenge tests; visit 2 was conducted after 2 to 4 weeks of treatment with fluticasone, 250 g twice daily. Patients returned to the clinic 2 to 7 days after visit 2 and were randomized to receive either fluticasone/salmeterol, 250/50 g twice daily, or fluticasone, 250 g twice daily. At 1 and 8.5 hours after the initial dose of blinded study medication was administered, patients performed a stepped exercise challenge test similar to that performed at visits 1 and 2. After 4 weeks of treatment, the final exercise challenge tests were performed 1 and 8.5 hours after the last dose of blinded study medication was administered. Throughout the study, patients made daily recordings of their study medication use, rescue albuterol use, PEFR, and adverse events on diary cards. Exercise Challenge Testing The stepped exercise challenge test consisted of running on a treadmill; the speed and incline of the treadmill allowed the patient’s heart rate to reach 80% or more of maximum based on age and is similar to the challenge reported by Simons et al.14 To control for the effects of the temperature and humidity of the inspired air during exercise, the subjects inspired compressed air from a balloon reservoir bag (eg, a Douglas Bag) fitted with a 2-way, non-rebreathing valve and a mouth-
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piece or face mask. The temperature of the room was maintained at 20° C to 25° C. The guidelines for performing the stepped exercise challenge test were as follows: step 1 lasted 2 minutes, with a target heart rate of 50% of maximum for age achieved by a treadmill speed of 2.5 mph at no incline; step 2 lasted 2 minutes, with a target heart rate of 70% of maximum for age achieved by a treadmill speed of 66% of the target speed at an incline based on age; and step 3 lasted 6 minutes, with a target heart rate of 80% of maximum achieved by the target treadmill speed at an incline based on age. Progression between these steps was contingent on the absence of cardiovascular and pulmonary signs and symptoms. The subject’s electrocardiogram and heart rate were monitored continuously throughout the exercise challenge test. The treadmill incline did not exceed 15%. Subjects were permitted to eat a light meal between the 2 exercise challenge test assessments on treatment day 1 and at week 4, and the meal was to be completed at least 1 hour before the second exercise challenge test. Food and beverages that contain caffeine were not permitted, and each subject was to remain sedentary at the site between exercise challenge tests. Spirometry assessments were performed on treatment day 1 and at week 4: immediately before drug administration (double-blinded study medication), immediately before exercise challenge testing, and 5, 10, 15, 30, and 60 minutes after exercise challenge using standardized equipment. Triplicate FEV1 measurements were performed at each evaluation. The highest FEV1 at each evaluation was used. Before beginning the second exercise challenge evaluation on days 1 and 28 of treatment, a subject’s FEV1 must have returned to at least 65% of predicted. After completion of each exercise challenge, rescue with albuterol was required if a patient’s FEV1 decreased to 40% of predicted or less or, at the study investigator’s discretion, if a patient experienced significant worsening of asthma symptoms. Because residual therapeutic effects of the albuterol could persist and affect subsequent exercise challenge test results, patients were not permitted to complete the 8.5-hour exercise challenge if they received albuterol rescue after the 1-hour challenge. Treatments Fluticasone/salmeterol, 250/50 g twice daily (Advair Diskus; GlaxoSmithKline, Research Triangle Park, NC), and fluticasone, 250 g twice daily (Flovent Diskus; GlaxoSmithKline), were administered in a double-blind manner. All patients received albuterol (Ventolin Inhalation Aerosol; GlaxoSmithKline) to use as needed to relieve breakthrough symptoms. Statistical Methods Based on data from previous studies5,15 that evaluated exercise-induced bronchospasm, it was estimated that 85 patients per treatment arm would provide 90% power to detect a significant difference in maximal percentage decrease in
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FEV1 of 6% between the 2 treatment groups based on a 2-sample, 2-sided t test at a significance level of P ⱕ .05. The primary measure of efficacy was maximal percentage decrease in FEV1 after the 8.5-hour exercise challenge test on treatment day 1 and at week 4. At baseline and at each stage after exercise, the test with the best FEV1 was selected; maximal percentage decline in FEV1 was defined as the percentage change from the preexercise baseline FEV1 to the minimum FEV1, collected within 1 hour of exercise challenge testing (selecting the best effort at each time). Exercise challenge tests were performed 1 and 8.5 hours after the first dose of blinded study drug was administered on treatment day 1 and 1 and 8.5 hours after the last dose of blinded study drug was administered at week 4. For each 1- and 8.5-hour exercise challenge test on treatment day 1 and at week 4, preexercise baseline FEV1 was measured approximately 1 and 8.5 hours after administration of double-blinded study medication (ie, immediately before exercise challenge testing). Secondary analyses included a categorical evaluation of the maximal percentage decline in FEV1 after exercise challenge testing, the time to return to within 5% of the preexercise value, the change from baseline in morning PEFR during the 4 weeks of treatment, and the change from baseline in the percentage of albuterol rescue–free days (defined as a day with no supplemental albuterol use) over the 4 weeks of treatment. Recovery time was defined as the time to return to within 5% of the preexercise baseline value from the time of the maximal percentage decline and was estimated with linear interpolation. If a patient’s FEV1 did not decrease 5%, recovery time was set at 0 minutes. If a patient was rescued and did not perform a postexercise FEV1 measure or did not return to within 5% of the preexercise baseline value, recovery time was set at 80 minutes.
Analysis of covariance models that include terms for treatment, investigator, and baseline were used to perform between–treatment group comparisons of continuous variables. Treatment group comparisons of categorical variables were examined using the Cochran-Mantel-Haenszel test. All statistical tests used a 2-sided hypothesis of no difference between treatment groups at a significance level of P ⬍ .05. The primary population for all statistical analyses was the intent-to-treat (ITT) population, which consisted of all patients randomized to receive study drug. All data collected for these patients, including those who discontinued study participation, were included. RESULTS A total of 192 patients were randomized to double-blind treatment: 102 to fluticasone/salmeterol, of whom 98 (96%) completed the study, and 90 to fluticasone, of whom 87 (97%) completed the study. The treatment groups were similar at baseline with respect to demographics, asthma and smoking history, and pulmonary function (Table 1). At screening, patients in both groups had a mean FEV1 of 78% of predicted, and mean ⫾ SEM maximal decreases in FEV1 after exercise challenge were 31.8% ⫾ 0.9% and 31.4% ⫾ 1.0% in the fluticasone/salmeterol and fluticasone groups, respectively. Most patients (82%) were using fluticasone before enrollment. Exercise Challenge Testing At visit 2, which was after 2 to 4 weeks of treatment with fluticasone, 250 g twice daily, values for the mean ⫾ SEM maximal decline in FEV1 after exercise challenge were 29.1% ⫾ 0.9% and 31.2% ⫾ 1.1% for patients who subsequently
Table 1. Baseline Demographic and Clinical Characteristics of the Study Population Characteristic Age, mean (range), y Women, % Race/ethnicity, No. (%) White Black Asian Hispanic Other Never used tobacco, %* History of asthma ⱖ 15 y, % Asthma-related emergency care, previous year, % Asthma-related hospitalization, previous year, % FEV1, mean ⫾ SEM, L FEV1, mean ⫾ SEM, % predicted Maximal postexercise decline in FEV1 at screening, mean ⫾ SEM, %
Fluticasone/salmeterol, 250/50 g (n ⴝ 102)
Fluticasone, 250 g (n ⴝ 90)
29 (12–50) 65 (64)
29 (12–50) 52 (58)
77 (75) 16 (16) 1 (⬍1) 6 (6) 2 (2) 83 64 18 6 2.72 ⫾ 0.06 78.2 ⫾ 0.7 31.8 ⫾ 0.9
62 (69) 22 (24) 0 4 (4) 2 (2) 87 54 11 3 2.72 ⫾ 0.07 77.8 ⫾ 0.8 31.4 ⫾ 1.0
Abbreviation: FEV1, forced expiratory volume in 1 second. * Patients were excluded if they had more than 10 pack-years of smoking or had smoked in the past year.
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were randomized to receive fluticasone/salmeterol and fluticasone, respectively. At visit 3 (treatment day 1), values for the mean ⫾ SEM maximal decline in FEV1 1 and 8.5 hours after administration of the first dose of study medication were 11.4% ⫾ 1.5% and 11.6% ⫾ 1.4%, respectively, for fluticasone/salmeterol and 20.0% ⫾ 1.7% and 12.6% ⫾ 1.6%, respectively, for fluticasone (P ⬍ .001 for comparison of fluticasone/salmeterol and fluticasone at 1 hour and P ⫽ .44 at 8.5 hours) (Fig 1). At week 4, values for the mean ⫾ SEM maximal decline in FEV1 at 1 and 8.5 hours after administration of the last dose of study medication were 10.9% ⫾ 1.5% and 8.9% ⫾ 1.1%, respectively, for fluticasone/salmeterol and 18.4% ⫾ 1.8% and 12.9% ⫾ 1.4%, respectively, for fluticasone (P ⱕ .01 for comparisons of fluticasone/salmeterol and fluticasone at 1 and 8.5 hours) (Fig 1). A significantly greater percentage of patients in the fluticasone group did not complete the 8.5hour exercise challenge test on day 1 or at week 4 compared with the fluticasone/salmeterol group (P ⱕ .01). Specifically, on treatment day 1 and at week 4, 36% and 33% of patients, respectively, in the fluticasone group did not complete the 8.5-hour exercise challenge test. By contrast, 18% of patients treated with fluticasone/salmeterol did not complete the 8.5hour exercise challenge test on treatment day 1 and at week 4. The primary reason patients did not complete the 8.5-hour challenge was the use of albuterol after the 1-hour challenge according to protocol-defined rescue criteria. On treatment day 1, 76% and 82% of patients in the fluticasone/salmeterol group had less than a 20% decrease in FEV1 after the 1- and 8.5-hour exercise challenges, respectively, compared with 54% and 81% of patients in the fluti-
casone group (P ⬍ .001 at 1 hour). At week 4, 80% and 90% of patients in the fluticasone/salmeterol group had less than a 20% decrease in FEV1 after the 1- and 8.5-hour exercise challenges, respectively, compared with 60% and 78% of patients in the fluticasone group (P ⱕ .04 at 1 and 8.5 hours). Additional categorical analyses of patients by maximal decline in FEV1 are given in Table 2. Recovery time, expressed as the time to return to within 5% of the preexercise, postdose baseline values from the maximum percentage decline in FEV1, is given in Table 3. On day 1 and at week 4, mean ⫾ SEM recovery times after the 1- and 8.5-hour challenges ranged from 17.1 ⫾ 2.9 to 22.4 ⫾ 3.1 minutes for the fluticasone/salmeterol group and 28.0 ⫾ 3.9 to 33.7 ⫾ 3.4 minutes for the fluticasone group (P ⱕ .045 for the 1-hour comparisons on day 1 and at week 4 and for the 8.5-hour comparisons at week 4). PEF and Albuterol Use Baseline mean ⫾ SEM values for morning PEFR were similar: 399.7 ⫾ 10.1 L/min and 426.4 ⫾ 13.7 L/min for the fluticasone/salmeterol and fluticasone groups, respectively. Over the 4-week treatment period, patients receiving fluticasone/salmeterol had a significantly greater mean ⫾ SEM increase in morning PEFR (19.2 ⫾ 3.4 L/min) compared with patients receiving fluticasone (6.3 ⫾ 4.1 L/min) (P ⫽ .03). The mean ⫾ SEM percentage of albuterol rescue–free days was also similar between the 2 treatment groups at baseline: 17.0% ⫾ 2.7% and 13.1% ⫾ 2.2% for the fluticasone/salmeterol and fluticasone groups, respectively. During the 4-week treatment period, patients in the fluticasone/salmeterol group
Figure 1. Mean maximal percentage decline in forced expiratory volume in 1 second after exercise challenge testing at 1 and 8.5 hours on treatment day 1 and at week 4 in the fluticasone/salmeterol, 250/50 g, and fluticasone, 250 g, groups. Asterisk indicates P ⱕ .01 vs fluticasone; dagger, P ⫽ .44 vs fluticasone. Error bars represent SEM.
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Table 2. Categorical Analysis of Patients by Percentage Decrease in Postexercise FEV1 1h Characteristic
8.5 h
Fluticasone, Fluticasone/salmeterol, Fluticasone, Fluticasone/salmeterol, 250 g (n ⴝ 90) 250/50 g (n ⴝ 102) 250 g (n ⴝ 90) 250/50 g (n ⴝ 102)
Patients completing the exercise challenge, No.* Postexercise decrease in FEV1, No. (%) ⬍10% 10% to ⬍15% 15% to ⬍20% 20% to ⬍25% ⱖ25%
Treatment day 1 90
100
84
58
45 (54) 14 (17) 10 (12) 4 (5) 11 (13)
29 (50) 10 (17) 8 (14) 4 (7) 7 (12)
59 (59) 14 (14) 3 (3) 7 (7) 17 (17)
32 (36) 6 (7) 11 (12) 9 (10) 32 (26)
98
86
84
60
66 (67) 11 (11) 1 (1) 5 (5) 15 (15)
35 (41) 10 (12) 7 (8) 3 (3) 31 (36)
59 (70) 10 (12) 7 (8) 2 (2) 6 (7)
30 (50) 10 (17) 7 (12) 4 (7) 9 (15)
Week 4 Patients completing the exercise challenge, No.* Postexercise decrease in FEV1, No. (%) ⬍10% 10% to ⬍15% 15% to ⬍20% 20% to ⬍25% ⱖ25%
Abbreviation: FEV1, forced expiratory volume in 1 second. *Two and 4 patients in the fluticasone/salmeterol group did not complete the 1-hour challenge on treatment day 1 and at week 4, respectively; 4 patients in the fluticasone group did not complete the 1-hour challenge at week 4. Table 3. Postexercise Recovery Time* Exercise challenge Treatment day 1 1h 8.5 h Week 4 1h 8.5 h
Fluticasone/salmeterol, 250/50 g
Fluticasone, 250 g
Patients, No.†
Recovery time, mean ⴞ SEM, min
Patients, No.†
Recovery time, mean ⴞ SEM, min
P value
102 87
19.7 ⫾ 2.8 22.4 ⫾ 3.1
90 66
33.7 ⫾ 3.4 28.0 ⫾ 3.9
.002 .562
98 87
18.5 ⫾ 2.8 17.1 ⫾ 2.9
87 67
31.7 ⫾ 3.4 28.6 ⫾ 3.8
.009 .045
* Recovery time was defined as the time to return to 5% of the preexercise baseline value from the time of the maximal percentage decline and was estimated using linear interpolation. † The number of patients who initiated an exercise challenge.
experienced a significantly greater increase in the mean ⫾ SEM percentage of rescue-free days vs patients in the fluticasone group (15.8% ⫾ 2.8% vs 7.6% ⫾ 2.9%; P ⫽ .02) (Fig 2). Adverse Events During the double-blind treatment period, 28 patients (27%) in the fluticasone/salmeterol group and 24 patients (27%) in the fluticasone group reported at least 1 adverse event. Adverse events reported by 3% or more of patients in either treatment group were headaches (6% with fluticasone/salmeterol and 4% with fluticasone), common cold (3% in each treatment group), upper respiratory tract infection (⬍1% with fluticasone/salmeterol and 4% with fluticasone), and sore throat (⬍1% with fluticasone/salmeterol and 3% with fluticasone).
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Seven patients (7%) receiving fluticasone/salmeterol and 4 (4%) receiving fluticasone reported adverse events that were considered by the reporting investigator to be drug related. Drug-related adverse events reported by more than 1% of patients in either treatment group were Candida (2% and 1% in the fluticasone/salmeterol and fluticasone groups, respectively) and headaches (3% and 0% in the fluticasone/salmeterol and fluticasone groups, respectively). Two patients (2%) receiving fluticasone/salmeterol and 1 (1%) receiving fluticasone were withdrawn from the study due to an adverse event. In the fluticasone/salmeterol group, 1 patient was withdrawn to undergo elective cosmetic surgery and 1 for “fainting,” which was considered by the investigator to possibly be related to the study medication. One patient in the fluticasone group withdrew because of symptoms associated with a viral upper respiratory tract infection. All
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Figure 2. Mean percentage of rescue-free days over 4 weeks of treatment. Asterisk indicates P ⱕ .04 for fluticasone/salmeterol, 250/50 g, vs fluticasone, 250 g.
events resolved by the end of the study. Only 1 exacerbation of asthma was reported in this study. It occurred in a patient in the fluticasone/salmeterol group and was due to a respiratory tract infection. There were no serious adverse events. DISCUSSION The results of this study demonstrate that in patients who were using moderate-dose inhaled corticosteroids for treatment of persistent asthma and demonstrated a decrease in FEV1 of at least 20% after exercise challenge before randomization, treatment with fluticasone/salmeterol protected against exercise-induced bronchospasm in most patients 1 and 8.5 hours after drug administration. Compared with fluticasone, the protective effect was greatest after 1 hour of treatment, with smaller differences observed after 8.5 hours. However, the protective effects of fluticasone/salmeterol therapy at 1 and 8.5 hours were sustained during long-term dosing, showing no evidence of diminution of effect during the 4-week study. The results of the present study need to be evaluated in light of differences in study design between this study and other exercise challenge studies. First, treatments for exercise-induced bronchospasm are most often studied in patients with near-normal lung function. Such patients have asthma symptoms that are triggered primarily by exercise, and they often have few, if any, other symptoms or persistent asthma.5,15–20 By contrast, patients in the present study had moderate persistent asthma, and they all required moderate doses of inhaled corticosteroids at study entry. Note that patients with persistent asthma who require daily controller therapy can experience worsening asthma symptoms that are triggered by activity or exercise as well as other common asthma triggers.3 This was true of the patients in this study, who had not only significant decreases in FEV1 after exercise challenge testing but also less than 20% rescue-free days during the run-in period.
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Second, the decreases in FEV1 observed after exercise challenge testing were greater in this study than have been reported in previous studies,5,15,16 in which patients generally had characteristics of mild asthma (baseline FEV1, 85%– 89% of predicted). For example, Kemp et al5 demonstrated that 30 minutes after dosing with salmeterol, 50 g, mean maximal percentage declines in FEV1 were only 5%. Likewise, Newnham et al16 evaluated the effect of salmeterol therapy on exercise-induced bronchospasm and found that the mean maximal percentage fall in FEV1 was only 0.8% an hour after drug administration. Similar results have been shown in pediatric patients with mild asthma.15 Relative to the present study, the smaller declines in FEV1 demonstrated in these other studies may, in part, reflect differences in baseline asthma severity in the study populations. Finally, inclusion of patients with moderate persistent asthma had a major impact on the ability of patients to complete 2 exercise challenge tests on the same treatment day. This was a more prominent finding in the fluticasone group. Approximately twice the number of patients in the fluticasone group did not complete the 8.5-hour exercise challenge on treatment day 1 and at week 4 (36% and 33%, respectively) compared with the fluticasone/salmeterol group (18% at each visit). This disparity was likely due to a lower level of protection against exercise-induced bronchospasm with fluticasone alone for the patient population as a whole. In the fluticasone group, the decreases in FEV1 at the 1-hour challenge (mean, 19.2%) were greater than at the 8.5-hour challenge (mean, 12.8%). This is in contrast to the fluticasone/salmeterol group, in which the decrease in FEV1 at 1 and 8.5 hours was similar (mean, 11.2% and 10.3%, respectively). Thus, the treatment differences were smaller between fluticasone/salmeterol and fluticasone at 8.5 hours compared with at 1 hour. The smaller treatment difference at 8.5 hours was not due to a loss of effectiveness with fluticasone/salmeterol. Rather, the smaller treatment difference was due to the fact
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that many patients with the greatest reductions in FEV1 after the 1-hour challenge in the fluticasone group had to be rescued with albuterol and thus did not participate in the 8.5-hour challenge. The difference in response at 1 and 8.5 hours with fluticasone is difficult to explain pharmacologically, because the effect of fluticasone should not differ during this short period. Analysis of patients in the fluticasone group who completed both exercise challenges indicates that they had similar responses at 1 and 8.5 hours. For these completers, an average decrease in FEV1 of 12.8% was observed at 1 and 8.5 hours on treatment day 1. For the fluticasone/salmeterol group, the mean decrease in FEV1 at 1 and 8.5 hours for patients who completed both challenges averaged 7.5% and 10.3%, respectively. Similar to the findings in the ITT population, these reductions were significantly less compared with those in the fluticasone group at all times except 8.5 hours on treatment day 1 (P ⱕ .01). Thus, in the ITT population and in the subgroup of the ITT population that completed both challenges, a significantly greater protective effect was observed with fluticasone/salmeterol therapy 8.5 hours after administration of the last dose of study medication, indicating that the protective effect of this drug was maintained with regular use. Patients who completed both exercise challenge tests had a different exercise response compared with those who completed only the 1-hour challenge. For example, patients in the fluticasone/salmeterol (14%) and fluticasone (29%) groups who completed only the 1-hour challenge had mean maximal declines in FEV1 of 33.5% and 31.9%, respectively. For these patients, neither treatment provided adequate protection against exercise-induced bronchospasm based on the study protocol (ie, decrease in FEV1 to ⱕ40% of predicted or based on investigator discretion for worsening symptoms of asthma), and additional treatment was required. If these patients had completed both exercise challenges, it is unclear whether the results of this study would have differed. However, it would likely have resulted in a greater mean decrease in the fluticasone group due to the greater number of patients who did not complete the second exercise challenge compared with the fluticasone/salmeterol group. The salmeterol component of fluticasone/salmeterol is indicated for the treatment of exercise-induced bronchospasm, and a single dose of salmeterol provides protection in most patients for up to 12 hours.5,15,16 Long-term dosing studies10,18 –21 have shown a diminution of effect with the use of inhaled long-acting 2-agonists over time. However, long-term use of long-acting -agonists as monotherapy for exercised-induced bronchospasm in patients with persistent asthma is not appropriate, so the applicability of many of these previous studies to patients with persistent asthma is limited. Inhaled corticosteroids have been shown to reduce the severity of exercise-induced bronchospasm.6 –9 The mechanism of action for inhaled corticosteroids in this setting is less clear than the mechanism of action for -agonists but is likely due to nonspecific reductions in bronchial hyperresponsiveness and reduced inflammation.21–24 However, regardless of
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the precise mechanism, optimal benefit is obtained when an inhaled corticosteroid is used in combination with an inhaled long-acting -agonist. In conclusion, the results of this study demonstrate that regular use of fluticasone/salmeterol, 250/50 g twice daily, resulted in protection against exercise-induced bronchospasm in patients using moderate-dose inhaled corticosteroids for the treatment of persistent asthma. Significantly greater protection was observed with fluticasone/salmeterol therapy 8.5 hours after administration of the last treatment dose at week 4 compared with fluticasone therapy, indicating that the protective effect of fluticasone/salmeterol was maintained with long-term dosing. These results suggest that patients with persistent asthma, for whom physical activity is a trigger of asthma symptoms, may receive additional benefit from the use of fluticasone/salmeterol. ACKNOWLEDGMENTS We thank Shawn Jones, Patricia Matthews, Laura Sutton, and Cedric Grigg for assisting with the preparation of the manuscript and the following clinical investigators for their expertise and contributions: Theodore Lee, MD, Steven F. Weinstein, MD, Andrew J. Pedinoff, MD, Paul Chervinsky, MD, William W. Busse, MD, Edward Kerwin, MD, Frank S. Virant, MD, Arthur C. DeGraff, MD, Tom Harper, MD, Kenneth T. Kim, MD, David S. Pearlman, MD, Edward LeDoux, MD, Robert Noveck, MD, Sheldon Spector, MD, David I. Bernstein, MD, Edwin A. Bronsky, MD, Jonathan Corren, MD, Michael Natalino, MD, Anjuli Nayak, MD, Richard Rosenthal, MD, William N. Sokol, MD, Martha White, MD, Richard ZuWallack, MD, John Andrew Grant, MD, Craig F. LaForce, MD, Richard Weber, MD, Charles Fogarty, MD, Barry Miskin, MD, Jacob L. Pinnas, MD, Eugene F. Schwartz, MD, David Elkayam, MD, Harold B. Kaiser, MD, Phillip E. Korenblat, MD, Nancy K. Ostrom, MD, Michael P. Pacin, MD, Lewis Smith, MD, and Mark Wencel, MD. REFERENCES 1. Shapiro G, Lumry W, Wolfe J, et al. Combined salmeterol 50 g and fluticasone propionate 250 g in the Diskus device for the treatment of asthma. Am J Respir Crit Care Med. 2000;161: 527–534. 2. Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2000;105: 1108 –1116. 3. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; April 1997. 4. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; February 2002. NIH publication 02–3659. 5. Kemp JP, Dockhorn RJ, Busse WW, Bleecker ER, Van As A. Prolonged effect of inhaled salmeterol against exercise-induced
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6.
7.
8.
9.
10. 11. 12. 13. 14.
15.
bronchospasm. Am J Respir Crit Care Med. 1994;150: 1612–1615. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. Thorax. 1991;46:811– 816. Freezer NJ, Croasdell H, Doull IJ, Holgate ST. Effect of regular inhaled beclomethasone on exercise and methacholine airway responses in school children with recurrent wheeze. Eur Respir J. 1995;8:1488 –1493. Vidal C, Fernandez-Ovide E, Pineiro J, Nunez R, GonzalezQuintela A. Comparison of montelukast versus budesonide in the treatment of exercise-induced bronchoconstriction. Ann Allergy Asthma Immunol. 2001;86:655– 658. Hofstra WB, Neijens HJ, Duiverman EJ, et al. Dose-responses over time to inhaled fluticasone propionate treatment of exercise- and methacholine-induced bronchoconstriction in children with asthma. Pediatr Pulmonol. 2000;29:415– 423. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987;136:225–244. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meets ATS recommendations. Am Rev Respir Dis. 1981;123:659 – 664. Polgar G, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia, PA: WB Saunders Co; 1971. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis. 1991;144:1202–1208. Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exerciseinduced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics. 1997;99:655– 659. Blake K, Pearlman DS, Scott C, Wang Y, Stahl E, Arledge T. Prevention of exercise-induced bronchospasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol. Ann Allergy Asthma Immunol. 1999;82:205–211.
16. Newnham DM, Ingram CG, Earnshaw J, Palmer JB, Dhillon DP. Salmeterol provides prolonged protection against exerciseinduced bronchoconstriction in a majority of patients with mild, stable asthma. Respir Med. 1993;87:439 – 444. 17. Nelson J, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden ER Jr. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med. 1998;339:141–146. 18. Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Ann Intern Med. 2000;132:97–104. 19. Villaran C, O’Neill SJ, Helbling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol. 1999;104:547–553. 20. Garcia R, Guerra P, Feo F, et al. Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm. J Investig Allergy Clin Immunol. 2001;11:176 –182. 21. Trigg CJ, Manolitsas ND, Wang J, et al. Placebo-controlled immunopathologic study of 4 months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17–22. 22. Olivieri D, Chetta A, Del Donno M, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebocontrolled study. Am J Respir Crit Care Med. 1997;155: 1864 –1871. 23. Barnes PJ. Current issues for establishing inhaled corticosteroids as the antiinflammatory agents of choice in asthma. J Allergy Clin Immunol. 1998;101:427– 433. 24. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054 –1063.
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